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In situ vaccine application of inactivated CPMV nanoparticles for cancer immunotherapy.

ABSTRACT: Cowpea mosaic virus (CPMV) is currently in the development pipeline for multiple biomedical applications, including cancer immunotherapy. In particular the application of CPMV as in situ vaccine has shown promise; here the plant viral nanoparticle is used as an adjuvant and is injected directly into a tumor to reverse immunosuppression and prime systemic anti-tumor immunity. Efficacy of this CPMV-based cancer immunotherapy has been demonstrated in multiple tumor mouse models and canine cancer patients. However, while CPMV is non-infectious to mammals, it is infectious to legumes and therefore, from a safety perspective, it is desired to develop non-infectious CPMV formulations. Non-infectious virus-like particles of CPMV devoid of nucleic acids have been produced; nevertheless, efficacy of such empty CPMV nanoparticles does not match efficacy of nucleic acid-laden CPMV. The multivalent capsid activates the innate immune system through pathogen pattern recognition receptors (PRRs) such as toll-like receptors (TLRs); the RNA cargo provides additional signaling through TLR-7/8, which boosts the efficacy of this adjuvant. Therefore, in this study, we set out to develop RNA-laden, but non-infectious CPMV. We report inactivation of CPMV using UV light and chemical inactivation using β-propiolactone (βPL) or formalin. 7.5 J cm^-2 UV, 50 mM βPL or 1 mM formalin was determined to be sufficient to inactivate CPMV and prevented plant infection. We compared the immunogenicity of native CPMV and inactivated CPMV formulations in vitro and in vivo using RAW-Blue™ reporter cells and a murine syngeneic, orthotropic melanoma model (using B16F10 cells and C57BL6 mice). While the in vitro assay indicated activation of the RAW-Blue™ reporter cells by formaldehyde and UV-inactivated CPMV at levels comparable to native CPMV; βPL-inactivated CPMV appeared to have diminished activity. Tumor mouse model experiments indicate potent efficacy of the chemically-inactivated CPMV (UV-treated CPMV was not tested) leading to tumor regression and increased survival; efficacy was somewhat reduced when compared to CPMV, however these samples outperformed the empty CPMV nanoparticles. These results will facilitate the translational development of safe and potent CPMV-based cancer immunotherapies.

SUBMITTER: Chariou PL

PROVIDER: S-EPMC8323807 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In situ vaccination for cancer immunotherapy uses intratumoral administration of small molecules, proteins, nanoparticles, or viruses that activate pathogen recognition receptors (PRRs) to reprogram the tumor microenvironment and prime systemic antitumor immunity. Cowpea mosaic virus (CPMV) is a plant virus that─while noninfectious toward mammals─activates mammalian PRRs. Application of CPMV as in situ vaccine (ISV) results in a potent and durable efficacy in tumor mouse models and canine patients; data indicate that CPMV outperforms small molecule PRR agonists and other nonrelated plant viruses and virus-like particles (VLPs). In this work, we set out to compare the potency of CPMV versus other plant viruses from the Secoviridae. We developed protocols to produce and isolate cowpea severe mosaic virus (CPSMV) and tobacco ring spot virus (TRSV) from plants. CPSMV, like CPMV, is a comovirus with genome and protein homology, while TRSV lacks homology and is from the genus nepovirus. When applied as ISV in a mouse model of dermal melanoma (using B16F10 cells and C57Bl6J mice), CPMV outperformed CPSMV and TRSV─again highlighting the unique potency of CPMV. Mechanistically, the increased potency is related to increased signaling through toll-like receptors (TLRs)─in particular, CPMV signals through TLR2, 4, and 7. Using knockout (KO) mouse models, we demonstrate here that all three plant viruses signal through the adaptor molecule MyD88─with CPSMV and TRSV predominantly activating TLR2 and 4. CPMV induced significantly more interferon β (IFNβ) compared to TRSV and CPSMV; therefore, IFNβ released upon signaling through TLR7 may be a differentiator for the observed potency of CPMV-ISV. Additionally, CPMV induced a different temporal pattern of intratumoral cytokine generation characterized by significantly increased inflammatory cytokines 4 days after the second of 2 weekly treatments, as if CPMV induced a "memory response". This higher, longer-lasting induction of cytokines may be another key differentiator that explains the unique potency of CPMV-ISV.

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In situ vaccine application of inactivated CPMV nanoparticles for cancer immunotherapy.

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